Many of the arterial-wall cell types thought to be responsible for the oxidation of low-density lipoprotein (LDL) either generate nitric oxide constitutively, or can be induced to generate nitric oxide by lipopolysaccharide and cytokines. The stimulation of mouse peritoneal macrophages has previously been shown to inhibit the oxidative modification of LDL by these cells in a process that is dependent on nitric oxide synthesis. We have incubated LDL with various nitric oxide donors in vitro. We have shown that nitric oxide is unable to oxidize or modify LDL and that the NO-donor compounds S-nitrosoacetyl penicillamine (SNAP), spermine NONOate (SNN), and S-nitrosoglutathione (GSNO) are able to inhibit copper-, azo initiator-, and macrophage-dependent oxidation of LDL. We have also examined the effect of nitric oxide donors on the toxicity of photo-oxidized LDL to selenium-deficient endothelial cells and found that GSNO and SNN inhibit this. We hypothesize that nitric oxide is acting, in all the above cases, by inhibiting the progression of lipid peroxidation. We envisage that nitric oxide is able to scavenge the propagatory peroxyl and alkoxyl radicals and, thus, is acting as a chain-breaking antioxidant. nitric oxide may well be a physiologically important antioxidant that plays an anti-atherogenic role.